Nearly half of adults have periodontitis, an inflammatory disease affecting the tissues that surround and support the teeth. The prevalence of periodontitis further increases in aged populations and in individuals with diabetes or history of smoking. It has been reported that approximately 50% of periodontitis patients aged 30 years and older have been reported to have alveolar bone loss that may lead to tooth loss and osseointegration failure of dental implants. Although current pharmacological therapies have been useful in the treatment of systemic osteoporosis, these treatments have limited efficacy for treating periodontitis-associated alveolar bone loss. Osteoimmunology has demonstrated that the imbalance and dysregulation of proinflammatory cytokines and bone metabolism mediators play critical roles in the development of periodontitis-associated bone loss by activating osteoclastogenesis and impairing bone formation. MicroRNAs (miRs), small non-coding RNAs, have been demonstrated to serve pro- and/or anti-inflammatory functions through modification of the activities of proinflammatory cytokines. miRs also participate in bone homeostasis by up- or down-regulating osteoblastic and osteoclastic differentiation. Our long-term goal is to develop a miR-based treatment that can arrest and regenerate inflammation-induced periodontal bone loss by utilizing specific miRs to inhibit inflammation and improve osteogenic differentiation. Our objective in this application is to establish a proof of concept in which miR-200c, a member of the miR-200 family, delivered using a non-viral vector can inhibit periodontitis- induced bone loss by both repressing osteoclastogenesis induced by proinflammatory molecules and bone metabolism mediators and enhancing bone formation. In this project, we will determine the molecular function and potential underlying mechanism(s) of miR-200c on major proinflammatory and bone resorption factors that participate in periodontitis-induced bone loss (Study-1) and the in vivo efficacy of miR-200c delivered by a non- viral gene delivery system to inhibit periodontal bone loss in a rat model of periodontitis (Study-2). At the completion of this project, it is our expectation that we will have significantly expanded our understanding of the role and underlying mechanism(s) mediated by miR-200c on osteogenic differentiation and proinflammatory and bone metabolism factors. We also seek to determine the translational capabilities of the miR-200c on re- pressing periodontal bone resorption and improving bone formation, which will provide guidelines to explore a novel therapeutic strategy to treat bone loss associated with periodontitis.